Saturday, January 11, 2014

Digoxin, digoxout: an appraisal of digoxin immune fab

Preface: The inspiration for this topic came from an exchange on Twitter between @PharmERToxGuy, @DavidJuurlink, and I, representing one of the things I love most about #hcsm -- the opportunity for dialogue across diverse backgrounds and practice settings. In this particular case, we debated the appropriate use of digoxin immune fab (DigiFab®), which was certainly challenging to do in segments of 140 characters or less. Below I have outlined a more detailed rationale for why I advocate its conservative use in the management of digoxin toxicity.

My reasons for advocating the conservative use of digoxin immune fab (DigiFab®) are unrelated to its efficacy, as it is undoubtedly the most effective antidote for digoxin toxicity. Instead, I contend that in many cases, it is an unnecessary and overly aggressive -- if not a costly -- approach to a scenario that may be just as effectively managed by thoughtful monitoring and supportive therapy. While it can be challenging to predict whether patients might require fab therapy at a later time, I believe a more judicious approach can be made possible by considering the severity of toxicity, the circumstances in which it occurred, and whether fab administration would substantially alter the clinical course of the patient.

Digoxin toxicity is difficult to characterize as a result of heterogeneity in the literature (e.g., study methods, definitions for toxicity) and how use of digoxin has evolved over time (i.e., patient populations, indications, dosing, target concentrations). As an example, a patient with a ventricular arrhythmia and serum digoxin concentration of 10.0 ng/mL in 1994 and one with symptomatic bradycardia and a serum digoxin concentration of 2.0 ng/mL in 2014 are both classified as having digoxin toxicity (and both cases often characterized simply as a dysrhythmia), although the severity of their presentations is vastly different. These and similar challenges may explain in part some of the discrepancies in the literature, as some studies demonstrate a decline in the prevalence of digoxin toxicity while others claim it has not changed [1-3].

What has changed considerably over the last several decades is how digoxin is used. In the late 1980s and early 1990s, it was not uncommon for the vast majority of patients with heart failure to be receiving digoxin therapy -- as many as 9 out of 10 in some studies [4]. Today those numbers are substantially fewer, as digoxin therapy is often reserved for those patients with advanced symptomatic disease. When it is used in this population, a lower serum concentration (i.e., 0.5 - 0.9 ng/mL) is targeted, ameliorating many of the more severe adverse effects observed in the setting of elevated concentrations in the past [5,6]. Additionally, patients with heart failure are likely to be on concomitant therapies (e.g., beta blockers, aldosterone antagonists, implantable defibrillators and other devices) that may confer protection from some of the more severe forms of digoxin toxicity or prevent it altogether (e.g., less hypokalemia as a result of aldosterone antagonist use). Similar trends, including a decline in overall digoxin use and reservation for only the most advanced cases, have also been observed in the atrial fibrillation population, where lenient rate control targets have obviated the need for digoxin in many patients [7-9].

Whether or not these differences impact the number of patients presenting with digoxin toxicity, they likely influence how, and perhaps more importantly, why patients present. In my practice setting, digoxin toxicity often manifests as a result of something more problematic (i.e., renal impairment as a result of worsening heart failure, emergence of underlying conduction abnormalities) rather than the consequence of a drug-drug interaction or acute overdose. In these latter cases, fab administration may be a reasonable approach for preventing hospital admission. However, for the 4 out of every 5 patients with digoxin toxicity who require hospitalization either way, fab administration may not confer substantial benefit over what would be provided by monitoring and symptomatic support [3].

Patients with worsening heart failure often require days of clinical evaluation whether or not they have signs or symptoms consistent with digoxin toxicity (which can often mimic those of worsening heart failure). Furthermore, complete digoxin withdrawal may actually worsen outcomes in this population [6, 10]. In the case of renal impairment, digoxin immune fab may not be an ideal strategy if renal impairment is advanced or does not improve substantially, as it too requires renal clearance and is not removed by hemodialysis. Although an earlier review substantiates fab use in patients with mild to moderate renal impairment, several limitations make it difficult to derive similar conclusions when renal impairment is severe [11]. Although manifestations of digoxin toxicity may initially improve in this latter population, recrudescent toxicity may occur days to weeks later as digoxin redistributes from peripheral tissues, a phenomenon that has been well-documented in the literature [12, 13]. For patients on chronic digoxin therapy, this may occur even in the absence of severe renal impairment. In these scenarios, fab use may provide clinicians with a false sense of security, resulting in less frequent monitoring or premature discharge when the patient should be observed for recrudescent toxicity or worsening signs and symptoms of heart failure.

Finally, as I alluded to in several instances above, digoxin immune fab may not be the most cost-effective strategy in a given patient. Notably, many cost-effectiveness analyses are a decade or more older, making them subject to the same limitations as the epidemiological studies described above. Given the financial woes of today's health care environment, cost-effectiveness should be a factor in determining whether a therapy is indicated, especially when less expensive alternatives exist or if the therapy is unlikely to alter the long-term outcome of the patient. Otherwise, we endanger our ability to use these more expensive therapies in patients who have no alternatives.  In the US, a single vial of digoxin immune fab costs between $1200-1500 (or more), and most patients require multiple vials based on their body weight and/or serum digoxin concentration. Unless hospitalization can be substantially shortened or avoided altogether, the cost of fab therapy may quickly outpace reimbursement. For example, the average reimbursement for a drug overdose at my institution runs about $6500, whereas a heart failure admission runs around $8300 [14].

That being said, the following are situations where I would definitely recommend the use of digoxin immune fab:
  • Ventricular arrhythmias, accelerated junctional rhythms
  • Life-threatening bradyarrhythmias unresponsive to chronotropic agents (and when temporary pacing is not readily available)
  • Acute mental status changes
  • Acute overdose
I generally avoid recommending fab on the basis of a specific serum digoxin concentration alone, as these are often open to interpretation (e.g., timing of ingestion, laboratory draw). Furthermore, a toxic concentration is any concentration that results in clinically meaningful adverse sequelae in a given patient. A serum digoxin concentration of 2.0 ng/mL resulting in a ventricular arrhythmia is toxic and requires emergent treatment, while a patient with a serum concentration of 4.0 ng/mL and no adverse sequelae requires close observation but emergent therapy is not warranted.

Outside the indications outlined above, the strategy I most commonly recommend for managing digoxin toxicity is to simply facilitate urine output (e.g., intravenous fluids), provide supportive therapy when necessary, and monitor closely should a need for fab arise. If the patient has symptomatic bradycardia, this may require intermittent use of a chronotropic agent. Although atropine is often recommended in this scenario, its half life makes it less than ideal for counteracting a drug that may require hours to days to clear. Instead, I prefer the use of a dopamine infusion in this setting, as it may be turned on or off (or titrated) based on patient need. Importantly, dopamine and other catecholamine-based therapies should be monitored closely so as not to exacerbate other rhythm disturbances commonly associated with digoxin toxicity.

Peer review: Special thanks goes to Jo Ellen Rodgers, PharmD, FCCP, BCPS (AQ Cardiology), a clinical associate professor at the University of North Carolina Eshelman School of Pharmacy, and Jonathan Cicci, PharmD, BCPS, a clinical pharmacy specialist in cardiology at the University of North Carolina Health Care for their review of this entry.

References
  1. Haynes K, Heitjan D, Kanetsky P, Hennessy S. Declining public health burden of digoxin toxicity from 1991 to 2004. Clin Pharmacol Ther. 2008 Jul;84(1):90–4.
  2. Yang EH, Shah S, Criley JM. Digitalis toxicity: a fading but crucial complication to recognize. Am J Med. 2012 Apr;125(4):337–43. 
  3. See I, Shehab N, Kegler SR, Laskar SR, Budnitz DS. Emergency Department Visits and Hospitalizations for Digoxin Toxicity: United States, 2005-2010. Circ Heart Fail. 2013 Dec 3; 
  4. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group. N Engl J Med. 1987 Jun 4;316(23):1429–35. 
  5. Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA J Am Med Assoc. 2003 Feb 19;289(7):871–8. 
  6. Ahmed A, Gambassi G, Weaver MT, Young JB, Wehrmacher WH, Rich MW. Effects of discontinuation of digoxin versus continuation at low serum digoxin concentrations in chronic heart failure. Am J Cardiol. 2007 Jul 15;100(2):280–4. 
  7. Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002 Dec 5;347(23):1825–33. 
  8. Hohnloser SH, Crijns HJGM, van Eickels M, Gaudin C, Page RL, Torp-Pedersen C, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med. 2009 Feb 12;360(7):668–78. 
  9. Van Gelder IC, Groenveld HF, Crijns HJGM, Tuininga YS, Tijssen JGP, Alings AM, et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med. 2010 Apr 15;362(15):1363–73. 
  10. Packer M, Gheorghiade M, Young JB, Costantini PJ, Adams KF, Cody RJ, et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. RADIANCE Study. N Engl J Med. 1993 Jul 1;329(1):1–7. 
  11. Wenger TL. Experience with digoxin immune Fab (ovine) in patients with renal impairment. Am J Emerg Med. 1991 Mar;9(2 Suppl 1):21–23; discussion 33–34. 
  12. Rajpal S, Beedupalli J, Reddy P. Recrudescent digoxin toxicity treated with plasma exchange: a case report and review of literature. Cardiovasc Toxicol. 2012 Dec;12(4):363–8. 
  13. Hazara AM. Recurrence of digoxin toxicity following treatment with digoxin immune fab in a patient with renal impairment. QJM Mon J Assoc Physicians. 2013 Sep 27; 
  14. Medicare C for, Baltimore MS 7500 SB, Usa M. Medicare Provider Charge Data Overview [Internet]. 2013 [cited 2013 Dec 24]. Available from: http://www.cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and-Reports/Medicare-Provider-Charge-Data/index.html

6 comments:

David Juurlink said...

Nice post Brent. While I agree we don't want to use an expensive antidote wastefully, I think being overly restrictive has its downsides too. And the idea of using atropine or dopamine instead of DigiFab raises a major antibody response here. I can't imagine not using immune Fab in such a case.

But here's a less dramatic scenario:

A 78 yo man on digoxin presents with fatigue x 3-4 days, HR 44 (sinus) but SBP is 110 mmHg and he has preserved mental status. [dig] 3.8, with some AKI (ClCr 22 ml/min.) Maybe the digoxin accumulated because of a P-gp inhibitor on top of the AKI, maybe not.

I would give this patient immune Fab.

My reasoning is that if you don't give it, you're going to end up monitoring the patient for a few days, perhaps on telemetry (and in some places this means a stepdown unit). But even if it's just a ward bed, how much will that cost?

Meanwhile, the patient's in a hospital bed waiting for C. diff, MRSA, a DVT, a fall, a medication error or some other bonus prize associated with his hospital stay. And maybe he's getting a little deconditioned in the process...

All this because we didn't want to spend $2000 (okay, perhaps more in the U.S) on an antidote that would take digoxin out of the picture?

If this person's primary reason for hospital admission was digoxin-related bradycardia, I can't endorse not using the antidote. Giving it in such a case is pragmatic, and may even be safer and less expensive than withholding it.

Brent N Reed said...

You make a fair point, and perhaps the patient described in this scenario represents the 1 in 5 with digoxin toxicity that does not require hospital admission. On the other hand, I would contend that the primary reason for his hospital admission is acute kidney injury – digoxin-induced bradycardia was simply the manifestation that brought him in. Similarly, I cannot imagine many scenarios where he would not be admitted for at least a day or two to investigate the etiology of acute kidney injury, irrespective of digoxin immune fab use. At his current rate of creatinine clearance, one should anticipate at least 20-25% digoxin elimination, which should only improve with the hydration he would expectedly receive for acute kidney injury. If an improvement in his symptoms correlates with resolving renal function, it should be safe to discharge him in a similar amount of time as long as he is hemodynamically stable. Even with fab administration, some symptoms may take days to resolve, so I see no need to keep him in the hospital as long as he is trending in the appropriate direction.

Assuming this patient would require admission, what would fab provide us? If his symptoms did not improve with its use, he would require more extensive evaluation, but the same could be said if they did not improve with drug withdrawal, hydration, and a subsequent improvement in renal function. Unless it saved a couple or more days of hospitalization, I doubt fab would be a very cost-effective strategy.

Using the same scenario, let’s say his symptoms improve with fab administration and he is monitored for a few hours in an observation unit and then discharged home. However, because the redistribution of digoxin from his peripheral tissues exceeds improvement in renal function (given he was not admitted/evaluated for this), it re-accumulates in the serum and he develops recrudescent digoxin toxicity. He returns to the hospital, only to be re-exposed to all of the dangers you mentioned, but this time the institution is not reimbursed by the third party payer because they claim the problem should have been addressed at his previous visit.

I can as easily imagine a scenario where he does not develop recrudescent digoxin toxicity but instead returns with atrial fibrillation or worsening heart failure because the rapid discharge facilitated by fab administration precluded a more cautious evaluation of his underlying disease and/or replacement of digoxin therapy. In the case of heart failure, an increased risk of rehospitalization following digoxin withdrawal is well documented in the literature [1,2].

While there are undoubtedly patients for whom fab represents the simplest and most pragmatic strategy for managing digoxin toxicity, I contend that these patients are becoming exceedingly rare. Most who require digoxin therapy have advanced cardiovascular disease, where toxicity is more often a surrogate marker for underlying problems requiring more extensive evaluation. In these scenarios, fab rarely represents a pragmatic treatment strategy, whereas premature discharge or the worsening heart failure or rate control that may result from withdrawal could be far worse than symptoms of toxicity.

References:
1. Packer M, Gheorghiade M, Young JB, Costantini PJ, Adams KF, Cody RJ, et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. RADIANCE Study. N Engl J Med. 1993 Jul 1;329(1):1–7.
2. Ahmed A, Gambassi G, Weaver MT, Young JB, Wehrmacher WH, Rich MW. Effects of discontinuation of digoxin versus continuation at low serum digoxin concentrations in chronic heart failure. Am J Cardiol. 2007 Jul 15;100(2):280-4.

Ryan Beechinor said...

Outstanding post and discussion for those of us who are trainees. Much appreciated!

Mahesh MSA said...

Nice post Brent.Thanks a lot for
sharing with us

Cardiology Hospitals in Hyderabad

ECG Interpretation said...

Nicely written blog which stresses the important point of aiming toward the conservative with regard to use of Digoxin Immune Fab. That said - I think the optimal approach is even more conservative than you expressed. I say this by emphasizing that Digoxin Immune Fab IS the intervention of choice when there is significant Dig Toxicity complicated by a truly life-threatening arrhythmia. BUT - “ventricular arrhythmias” encompasses a wide spread that includes isolated PVCs - “accelerated junctional rhythms” includes a usurping junctional rhythm in the 70-90/minute range that is not necessarily a dangerous rhythm - “life-threatening bradyarrhythmias” is far too vague a description to be useful (Is sinus brady at 45/minute included here ???? ) - “acute mental status changes” may be due to a myriad of factors in addition to Dig Toxicity - and “acute overdose” tells the reader little indeed about what is entailed.

Digoxin has linear pharmacokinetics. A patient whose half-life is estimated to be 3 days - and who begins with a serum Dig level = 4.0 ng/mL - will be down to a Dig level of ~ 2.0 ng/mL by 3 days later. Lots of factors enter into how to use that “dig level” the lab reports - such that a patient with sinus bradycardia in the 40’s - or accelerated junctional rhythm in the 80’s and a Dig level initially at 4.0 ng/mL may not be “in danger” for a very long period of time (even less perhaps than that initially calculated half-life, since their drug level is on the way down ...). In years past (I was trained during that period when virtually all of my heart failure patients were on the drug) - we did not yet have Digoxin Immune Fab - and RARE was the patient who did not present in flagrantly life-threatening arrhythmias (ie, bidirectional VT; complete AV block with extended pauses; ATach with block) who got into trouble. The vast majority of patients we’d admit for “Dig toxicity” simply wore off their drug over a few days and did fine (correcting volume status, treating heart failure, fixing electrolytes, etc. helped along the way) - without need for any immediate “antidote”. Even after Digoxin Immune Fab came out I found it usually not needed in most of the Dig Toxic patients we’d admit.

BOTTOM LINE: Digoxin Immune Fab may be a MAGIC drug. But much (most) of the time - it probably won’t be needed. Clearly - “Ya gotta be there” to make the decision as to whether or not to use Dig Immune Fab - but unless one of those flagrantly life-threatening Dig-Toxic arrhythmias is present - you usually will not need to.

THANKS again for addressing this important topic!

Brent N Reed said...

Thank you for stopping by and I appreciate the insights. I see your point about the criteria for fab use being a bit on the vague side -- it was done with the best of intentions. When I tried to make them more specific, I kept finding that I was listing scenarios in which the "danger" was really in the eye of the beholder (i.e., specific thresholds for heart rate). Perhaps some additional detail would be helpful, so I appreciate the specific examples you have listed.